Functions of Heparan Sulphate in the C. elegans Nervous System

My research is aimed at understanding the development of the nervous system at the molecular level. I am particularly interested in a group of complex glycoproteins, heparan sulphate proteoglycans (HSPGs). My research uses the nematode Caenorhabditis elegans as a simplistic genetic model.
Understanding neuronal development is one of the fundamental questions in biology as neurons control actions from movement to autonomous functions such as heart beat and breathing, and our ability to sense, think and remember. The adult human brain has over hundred billion neurons which each make connections with an average of 1000 target cells, yet mistakes happen very rarely. Neuron migration and formation of neuronal connections during development are genetically determined and dictate the wiring of the entire nervous system, yet the molecular mechanisms are still poorly understood.
HSPGs are present in cell membranes and in the extracellular space between cells. HSPGs mediate interactions of cells with their environment and play critical roles in regulating development and homeostasis. In the nervous system HSPGs guide migrating neurons and their processes, and control functions involved in learning and memory.
C. elegans contains homologues of key genes involved in human neuronal development. A simplified model is expected to improve understanding of HSPGs in normal cellular communication. Understanding normal development will provide novel insights into mechanisms that underlie cancer, degenerative neuronal diseases such as Alzheimer’s and Parkinson’s, and regeneration after injury.

Heparan sulfate proteoglycans (HSPGs) are ubiquitous glycoproteins of the cell surface and of the extracellular matrix that contain a protein core substituted with heparan sulfate (HS) polysaccharide chains. HS chains encode complex sugar sequences with variant sulfation patterns that confer biological functions as protein regulators. Thus HS/HSPGs play essential roles in controlling cell differentiation, tissue morphogenesis and homeostasis. In the nervous system, HS and HSPGs have been implicated in neuron migration, axon guidance, synapse formation and maturation and control of physiological responses such as feeding, learning and memory. The importance of HSPGs and HS has been highlighted by the findings that a number of human genetic disorders are associated with mutations in genes encoding for HSPGs or HS biosynthetic enzymes. Changes to the fine structure of HS in malignant transformation imply a role in cancer. Furthermore, HS and HSPGs control amyloid formation thus contributing to neurodegenerative diseases such as Alzheimer?s.
The C. elegans genome contains in most cases a single ortholog of vertebrate HSPGs and HS biosynthetic enzymes providing an excellent and uniquely tractable model to study the structural complexity of HSPGs in vivo without genetic redundancy. Importantly, there are existing mutant alleles available in all HSPG core proteins and in enzymes involved in biosynthesis and breakdown of HS. The proposed research exploits C. elegans as a model to resolve the functions of HS and HSPGs in neuronal development using a unique combination of molecular genetics and biochemistry. This will entail:
1. Biochemical identification of HSPGs and their function in the C. elegans nervous system especially in the context of neuron migration, axon outgrowth and synapse assembly
2. Structure-function relationship of HS using both genetic and biochemical approaches
3. Identification of the signalling pathways regulated by HS and HSPGs

As many of the basic biological signalling pathways are highly conserved from nematodes to mammals, results from this research are expected to uncover novel functions of HSPGs applicable to human biology, neuronal disorders and diseases, and into mechanisms controlling regeneration after injury.